The genetic basis of the neuroadaptive response to stress and anxiety relative to alcohol abuse is poorly understood. In this Research Component of the INIA, a wide net will be cast to identify genes important to neuroadaptation and alcohol abuse by using ethyl nitrosourea (ENU)-induced mutations of male mouse germ cells and subsequent breeding to screen for dominant and homozygous recessive mutations that result in aberrant alcohol-related phenotypes. Microarray and gene mapping studies are proposed to chart the molecular pathways and the specific genes that are involved in alcohol-related phenotypes. In addition, specially constructed congenic lines of mice will be used as reagents to better map loci responsible for quantitative trait loci (QTLS) and serve as reagents for gene identification in an ENU-mutagenesis program. In Aim, 1, ongoing NIH-supported mutagenesis program will be identifying mutants with abnormal fear conditioning behavior and a wide range of aberrant alcohol phenotypes and these mutants will be further explored for a) corticosterone levels following acute ethanol administration and b) stress-induced reinstatement of ethanol consumption. A concerted effort will be made in Aim 2 to identify the genetic basis of quantitative trait (QTLS) for alcohol-related behaviors by targeted mutagenesis of mouse chromosomes 1 and 4. Male congenic or consomic mice that span the withdrawal and drinking QTLs on Chr 1 and 4 will mutagenized with ENU. Test class mice, identified by molecular markers, will be phenotyped for 2-bottle choice, withdrawal or corticosterone levels following ethanol administration. Mice that show aberrant behavior in any of these tasks would be candidates to bear a mutation in a gene responsible for the relevant QTL. These studies should provide insights into the genetic bases of stress-alcohol interactions, and provide molecular clues to rational therapeutic approaches to curing alcoholism.